PROJECT SUMMARY/ABSTRACT Traumatic brain injury (TBI) is the leading cause of disability and death in people under 45 with approximately 10 million new cases each year worldwide. The effects of TBI can be severe, including neurocognitive, physical, and psychosocial impairment. There remains a significant unmet need to develop strategies to avoid long-term damage from TBI. The primary phase of TBI describes immediate neuronal damage from contusions or oxygen deprivation caused by global mass effect. Secondary injury occurs later via such mechanisms as reperfusion injury, delayed cortical edema, blood-brain barrier (BBB) breakdown, and local electrolyte imbalance. These disturbances result in increased reactive oxygen species (ROS), calcium release, glutamate toxicity, lipid peroxidation (LP), and mitochondrial dysfunction that lead to a vicious positive feedback loop of progressive oxidative stress-mediated neurodegeneration and neuroinflammation. Such secondary injury may occur in brain adjacent to the site of initial supposed injury, yielding unexpected spread of the zone of damage over months post-injury. With the goal of treating secondary brain injury, ROS scavengers and LP product inhibitors have become increasingly popular. However, there are still no effective treatment options demonstrating improved outcome in a large, multi-center Phase III trial, which can be partially attributed to poor delivery to and retention in the brain. Our overall goal is to reduce the long-term secondary injury phase of TBI using ROS and LP product reactive nanoparticles (NPs) that can quickly accumulate and be retained in damaged tissue to reduce post- traumatic oxidative stress. We have previously developed multifunctional, reactive NPs that aid in imaging distribution within the injury and result in reduced neuroinflammation and neurobehavioral deficits in a mouse model of TBI. We hypothesize that NP-mediated reduction oxidative stress in TBI will reduce long-term damage and improve recovery. This is based on the scientific premise of preclinical efficacy shown with ROS and LP product inhibitors as well as NP accumulation and retention in a TBI. To address our hypothesis, we will refine and optimize our modular, image-guided NPs to maximize uptake and retention within damaged brain in a controlled cortical impact mouse model of TBI in Aim 1. In Aim 2, we will study the effects of NP-mediated reduction in post-traumatic oxidative stress on the spread of secondary injury that will provide us a therapeutic index for these NPs and, and then in Aim 3 test neurobehavioral outcome. This proposal capitalizes on advances in nanotechnology that facilitate the development of novel approaches to treat and image TBI. If successful, these NPs could be further developed for other pathologies that involve progressive neuroinflammation and neurodegeneration.